Abstract
Glioma is the most prevalent primary brain tumor. Immune checkpoint blockade has made a great stride in mending patient’s clinical outcome for multiple types of cancers. However, PD-1, CTLA-4, or VEGF blockade exhibited only poor outcome in glioma patients. This study aimed to explore the expression and role of IgSF11, an emerging immune checkpoint and a ligand of VISTA, in human gliomas. IgSF11 mRNA expression was assessed in human glioma patients at different grades using 2 independent cohorts, a set of 52 Moroccan samples, including 20 glioma tissues, 22 PBMC samples taken before and 10 PBMC samples taken after surgery; and a series of 667 patients from TCGA. In parallel, immunohistochemistry was performed to evaluate IgSF11 protein staining. IgSF11 gene expression was significantly upregulated in high grade glioma tissues, compared to low grade. IgSF11 protein also showed a significant expression in low and high-grade gliomas. Interestingly, IgSF11 expression seemed to correlate positively with other critical immune checkpoints such as PD1, PDL-1, VISTA, and surprisingly negatively with CTLA-4. Although, T cell markers appeared higher in advanced gliomas, T cell-produced pro-inflammatory genes showed similar expression levels, highly likely because of the potent immunosuppressive microenvironment. Indeed, increased expression of IgSF11 in advanced human gliomas associated with a poor overall survival. Our data strongly suggest that IgSF11 is an immune checkpoint, which is upregulated in advanced human gliomas and contributes to the immunosuppressive state resulting in a poor clinical outcome in glioma patients. IgSF11 could be considered as a possible promising therapeutic target in advanced human gliomas.
Highlights
Immunotherapy can reach long-lasting tumor remission with minimal adverse effects through manipulating the immune system [1]
10 after surgery) and 10 healthy donors were analyzed. Messenger RNA (mRNA) expression Levels of immunoglobulin superfamily 11 gene (IgSF11) were evaluated by real time Reverse Transcription (RT)-Polymerase chain reaction (PCR)
IgSF11 transcripts were elevated in healthy donors, glioma tissues and peripheral blood mononuclear cell (PBMC) before surgery compared to PBMCs taken from patients after surgery (p = 0.0233), (p = 0.0055), and (p = 0.0235), respectively (Figure 1A)
Summary
Immunotherapy can reach long-lasting tumor remission with minimal adverse effects through manipulating the immune system [1]. In addition to its high frequency among all types of central nervous system tumors, glioma exhibits the most aggressive and lethal type of cancers [5, 6], glioblastoma (GBM) or glioma of grade IV, according to the World Health Organization (WHO) classification of tumors of the central nervous system (CNS) [7]. Despite conventional therapies such as surgical resection, concomitant chemoradiotherapy, and/or adjuvant chemotherapy, the prognosis of patients with GBM remains poor [8]. No obvious benefit of neoadjuvant nivolumab was obtained with resectable GBM, with a median overall survival of just 7.3 months [14]
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